Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Targeting PGE2 to treat sepsis-induced acute heart failure
R. Schell1, B. G. Niehaus2, C. Bolz2, C. Achilles2, F. Alban1, N. Frey1, J. Backs2
1Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Innere Medizin, Institut für experimentelle Kardiologie, Univesitäsklinikum Heidelberg, Heidelberg;

Introduction:

We recently unmasked a new link between inflammation and adverse cardiac remodeling via activation of the transcription factor myocyte enhancer factor 2 (MEF2). MEF2D mediates acute contractile dysfunction and is regulated by a signaling pathway consisting of PGE2, EP3-receptors, PKD and Rac1 leading to a nucleo-cytoplasmic shuttling of HDAC5 with subsequent activation of MEF2. On that account, we aimed to target inflammation induced acute heart failure by inhibition of PGE2 formation and EP-receptor activation in vivo. 


Results:

BALB/c-wildtype-mice were pre-treated with the irreversible, unselective and widely used COX-inhibitor Acetylsalicylic acid (ASA, 100mg/kg bodyweight) one hour prior to induction of an inflammatory acute heart failure model. This E. coli derived lipopolysaccharide (LPS) induced endotoxemia leads to an acute severe depression of left-ventricular function, which was markedly abolished by ASA-pretreatment (LVEF after 24 hours in the LPS-treated groups: 50% in contrast to 22% in sham-treated littermates). ASA-pretreatment almost completely diminished myocardial PGE2-levels and attenuated LPS-induced overexpression of typical target genes of MEF2 (e.g. Nur77), confirming that PGE2-driven activation of the described signaling pathway leads to reduced MEF2 activation and consecutively improved outcome in terms of left ventricular function. 


Conclusion:

We intended to provide new therapeutic targets in inflammation-induced acute heart failure and show that PGE2 accounts for acute contractile dysfunction. We therefore propose that PGE2-induced activation of EP-receptors and its downstream pathway(s) are new and promising targets to mediate changes in context-dependent transcriptional patterns of inflammatory acute heart failure.
https://dgk.org/kongress_programme/jt2022/aP871.html